This proposal will investigate the link between autoimmunity and pulmonary vascular disease in systemic sclerosis (scleroderma). We will use a large well-characterized population of scleroderma patients who will be followed prospectively at the Johns Hopkins Scleroderma Center to interrogate the question of how immune-mediated injury to the vasculature can occur and if this injury leads to pulmonary hypertension. We have discovered that Granzyme B (GrB), a protease released from cytotoxic lymphocytes, can cleave plasminogen and fibrillin-1, proteins known to be important to the integrity of the blood vessels. Our data suggest that GrB cleavage of plasminogen releases angiostatin, an angiostatic molecule that we find increased in the plasma our patients with scleroderma. We have additional evidence of an imbalance of circulating angiogentic factors that are known to regulate vascular remodeling and angiogenesis. We suspect that the pathological process damaging vessels in the lung of scleroderma patients is directly linked to an autoimmune mediated inflammatory process; that this process can be measured in the small volumes of blood from patients in real time; that products released by GrB cleavage will reflect this disease process before it is clinically apparent and therefore abnormal plasma levels of angiostatin and/or fragments of cleaved fibrillin-1 will predict the clinically important outcome of pulmonary hypertension and other vascular disease in scleroderma. The overall hypothesis in this project is that dysregulated angiogenesis occurs in scleroderma-associated pulmonary hypertension and is mediated and propagated by a cellular autoimmune process via the Granzyme B pathway. Specific Aim #1 will investigate specific regulators of angiogenesis as possible biomarkers for the development of pulmonary hypertension in a prospectively followed cohort of well-characterized patients with scleroderma by defining the clinical outcome new pulmonary hypertension using a pre-designed state-of-the-art clinical and laboratory measurements and correlating this outcome with the potential biomarkers of interest. Specific Aim #2 will define the role of GrB in generating angiostatin in patients with scleroderma pulmonary hypertension. Specific Aim #3 will define whether GrB cleaved fibrillin-1 can be detected in scleroderma in the circulation or relevant tissues.